Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Room 3-250, Lurie Research Building, 303 East Superior, Chicago, IL, 60611, USA.
Department of Pharmacology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
J Bioenerg Biomembr. 2017 Aug;49(4):325-333. doi: 10.1007/s10863-017-9718-8. Epub 2017 Jun 14.
It is becoming increasingly clear that mitochondria drive cellular functions and in vivo phenotypes by directing the production rate and abundance of metabolites that are proposed to function as signaling molecules (Chandel 2015; Selak et al. 2005; Etchegaray and Mostoslavsky 2016). Many of these metabolites are intermediates that make up cellular metabolism, part of which occur in mitochondria (i.e. the TCA and urea cycles), while others are produced "on demand" mainly in response to alterations in the microenvironment in order to participate in the activation of acute adaptive responses (Mills et al. 2016; Go et al. 2010). Reactive oxygen species (ROS) are well suited for the purpose of executing rapid and transient signaling due to their short lived nature (Bae et al. 2011). Hydrogen peroxide (HO), in particular, possesses important characteristics including diffusibility and faster reactivity with specific residues such as methionine, cysteine and selenocysteine (Bonini et al. 2014). Therefore, it is reasonable to propose that HO functions as a relatively specific redox signaling molecule. Even though it is now established that mtHO is indispensable, at least for hypoxic adaptation and energetic and/or metabolic homeostasis (Hamanaka et al. 2016; Guzy et al. 2005), the question of how HO is produced and regulated in the mitochondria is only partially answered. In this review, some roles of this indispensable signaling molecule in driving cellular metabolism will be discussed. In addition, we will discuss how HO formation in mitochondria depends on and is controlled by MnSOD. Finally, we will conclude this manuscript by highlighting why a better understanding of redox hubs in the mitochondria will likely lead to new and improved therapeutics of a number of diseases, including cancer.
越来越明显的是，线粒体通过指导代谢物的产生速率和丰度来驱动细胞功能和体内表型，这些代谢物被提议作为信号分子发挥作用（Chandel 2015；Selak 等人，2005；Etchegaray 和 Mostoslavsky 2016）。其中许多代谢物是构成细胞代谢的中间产物，其中一部分发生在线粒体中（即 TCA 和尿素循环），而另一些则是“按需”产生的，主要是响应微环境的变化，以便参与急性适应性反应的激活（Mills 等人，2016；Go 等人，2010）。活性氧（ROS）由于其短暂的性质，非常适合执行快速和瞬时信号传递（Bae 等人，2011）。过氧化氢（HO）尤其具有重要的特性，包括扩散性和与特定残基（如蛋氨酸、半胱氨酸和硒代半胱氨酸）更快的反应性（Bonini 等人，2014）。因此，有理由提出 HO 作为一种相对特异性的氧化还原信号分子发挥作用。尽管现在已经确立 mtHO 至少对于缺氧适应和能量和/或代谢稳态是不可或缺的（Hamanaka 等人，2016；Guzy 等人，2005），但关于 HO 如何在线粒体中产生和调节的问题仅得到部分回答。在这篇综述中，将讨论这种不可或缺的信号分子在驱动细胞代谢中的一些作用。此外，我们将讨论 HO 在线粒体中的形成如何取决于 MnSOD 并受其控制。最后，我们将通过强调为什么更好地理解线粒体中的氧化还原枢纽可能会导致许多疾病（包括癌症）的新的和改进的治疗方法来总结本文。
